Angelman syndrome is an autism spectrum disorder for which no effective treatment currently exists. Individuals with Angelman syndrome exhibit outwardly normal development during the first year of life, but then develop severe intellectual disabilities, seizures, EEG abnormalities, gait disturbances, disrupted sleep patterns, and profound language impairments (Zori et al., 1992; Lossie et al., 2001; Clayton-Smith and Laan, 2003; Williams, 2005; Dan, 2008; Pelc et al., 2008; Dan, 2009). These deficits are caused by maternal deletions or mutations of a single gene, the E3 ubiquitin ligase Ube3a, and can be modeled in Ube3a-deficient mice. Because the paternal allele of Ube3a is silenced in most neurons through epigenetic imprinting, lost function of the maternal allele eliminates Ube3a protein expression in neurons (FIG. 1). With a prevalence of 1:15,000 (Steffenburg et al., 1996; Dan, 2008) and an average cost of care of >$150,000/year per individual across a full lifespan (Angelman Syndrome Foundation), the health care costs of Angelman syndrome are immense, quite aside from the human cost.
Genetic engineering approaches were used to rescue the neurological deficits in Angelman syndrome model mice (van Woerden et al., 2007), but this approach relies on knocking out genes, making it impractical in humans. A pharmacological approach offers a more viable alternative. Only one clinical trial, which tested the effects of the methyl donors betaine and folic acid, has been performed in humans (Arn et al., 1998; Bacino et al., 2003), and it has not proved successful to date.
The present invention provides methods and compositions for unsilencing imprinted genes (e.g., the paternal allele of Ube3a silenced through epigenetic imprinting), thereby providing methods of treatment of genomic imprinting disorders, such as Angelman syndrome.